There is a high degree of co-morbidity between painful musculoskeletal disorders, such as fibromyalgia, and various painful abdominal disorders, such as irritable bowel syndrome and interstitial cystitis. These conditions are exacerbated by stress, and, like stress, gastrointestinal disorders are associated with increases in corticotropin-releasing factor (CRF) and urocortins. Many of urocortins' effects match symptoms of fibromyalgia syndrome in particular. First, the literature indicates that urocortins attenuate abdominal nociception and our preliminary data suggest that urocortins simultaneously induce musculoskeletal hyperalgesia. Second, urocortins inhibit circulating glucocorticoids, consistent with a diminished diurnal rhythm and attenuated cortisol response to stress in patients with fibromyalgia. Third, there are sex differences in the regulation of urocortin's synthesis in rodents, consistent with the higher incidence of fibromyalgia in females than males. Finally, our preliminary data suggest that tolerance does not develop to the hyperalgesic effect of urocortins, thus, repeated surges in their release may persistently induce hyperalgesia, consistent with the chronic nature of fibromyalgia. Because urocortins recapitulate many characteristics of fibromyalgia and are elevated in abdominal disorders, we hypothesize that increased activity of urocortins produces musculoskeletal mechanical hyperalgesia. To test this, we will determine whether urocortin II in mice models chronically painful conditions in humans in terms of gender sensitivity, duration, and pharmacologic sensitivity. We will 1) characterize the receptor population responsible for the hyperalgesic effects of urocortins, 2) assess the sensitivity of urocortin-induced hyperalgesia to antinociceptive compounds, and 3) investigate whether mice develop tolerance to urocortins or are capable of long-term hyperalgesic activity. Our studies will provide important information about a new biochemical mechanism of hyperalgesia, and they will be translational in the following ways: if urocortins produce widespread mechanical hyperalgesia, similar to symptoms of fibromyalgia: 1) this will justify studies in patients, 2), these data will define a possible causal relationship between stress, chronic widespread musculoskeletal pain, and painful abdominal disorders, and 3) these studies will provide a model to test clinical interventions that relieve widespread musculoskeletal pain in humans. PUBLIC HEALTH RELEVANCE Our studies will provide important mechanistic information about the role of urocortins in chronic musculoskeletal pain and potentially the role of urocortins in the pain associated with fibromyalgia. Our results will have three broad benefits to translational research in the area of pain: first, if urocortin II recapitulates the symptoms of fibromyalgia, this will support the possibility that urocortins contribute to symptoms of fibromyalgia and will justify studies in patients with this disorder; second, these data will deepen our understanding of the relationship between painful abdominal disorders and chronic musculoskeletal pain; and third, the effects of urocortin II in mice will provide a model that can be used to test potential therapies and clinical interventions that relieve widespread musculoskeletal pain in humans.